Sixty-two thousand new cases of prostate cancer are diagnosed yearly in the United States and 19,000 men die of this disease. While 60-70% of patients initially respond objectively to hormonal treatments, tumor recurrence, disease progression and death usually ensue within 1-5 years. Cytotoxic chemotherapy produces objective benefit but allows median survivals only slightly in excess of one year. Consequently, a great need exists for development and careful examination of innovative, experimental treatment strategies. In the proposed study, we will increase the susceptibility of androgen-dependent prostate tumor cells to chemotherapy by unique hormonal, cell kinetic approaches. As experimental models, we will utilize two transplantable rat prostate tumors, the poorly differentiated Noble rat tumor and the well differentiated Dunning R3227H tumor. These two neoplasms span the range of differentiation observed in human prostate cancer. We will systematically examine the effect on cellular replication of multiple regimens of androgen depletion followed by repletion with exogenous testosters or dihydrotestosterone. Measurement of 3H-thymidine labelling indices, estimates of growth fraction and quantitative morphometric analysis will allow determination of the exact effects of these manipulations on cellular division. With these studies, the optimum treatment regimens to recruit resting tumor cells into active cycle and to synchronize cells already in the proliferating pool can be determined. We will use these regimens to determine whether cytotoxic chemotherapy can be potentiated if given at the time of peak DNA synthesis as compared to administration at its nadir. Regimens of androgen depletion/repletion plus chemotherapy will then be studied systematically in the rodent and tested in a pilot trial in patients. In additional studies, a medical method of producing androgen depletion (i.e. medical castration) using the gonadotropin releasing hormones superagonist analog, Leuprolide, will be exploited as a pharmacologic means to induce synchronization and recruitment of prostate tumor cells. Using the two rat tumor models, we will determine the degree of potentiation of single and multiple agent chemotherapy induced by the Leuprolide medical castration. These studies, when completed, should provide solid evidence of the ability of androgen priming to sensitize prostate tumor tissue to cytotoxic chemotherapy.